We performed global gene expression profiling to complement the ongoing positional cloning effort to identify susceptibility genes for diabetes and its predictors, insulin resistance and obesity. To this end, we have examined gene expression profiles in tissue samples from non-diabetic full-blooded Pima Indians using differntial-display PCR and human oligonucleotide microarrays containing 6800 genes and 35000 expressed sequence tags (ESTs). To identify possible determinants of insulin resistance, independent of the effects of obesity, differentially expressed genes were identified in skeletal muscle samples from a group of equally obese Pimas, matched for obesity, age and sex. To identify possible determinants of obesity, we identified differentially expressed genes in isloated, subcutaneous, abdominal adipocytes from a group of severly obese and lean Pimas matched for age and sex. To identify genes that were potentially secondarily differentially expressed, (e.g. as a result of hyperinsulinemia), we also determined leveles of gene expression in pre-adipocytes grown from these same adipose tissue samples.